Lacking Overall IMspiration for Triplet Therapy in Melanoma? A Review of the Interim Analysis of IMspire150.

David M. Miller; Kevin S. Emerick; Vishal A. Patel; Sonia Cohen; Isaac Brownell; Donald P. Lawrence

Lacking Overall IMspiration for Triplet Therapy in Melanoma? A Review of the Interim Analysis of IMspire150.

2023

Melanoma

In this Perspectives on the Science piece, we reflect on the impact of the recently published article by Ascierto et al. in Lancet Oncology that provides interim results from IMspire150.

Authors

Affiliations

David M. Miller

Massachusetts General Hospital

Harvard Medical School

Kevin S. Emerick

Mass Eye and Ear

Harvard Medical School

Vishal A. Patel

GW School of Medicine & Health Sciences

Sonia Cohen

Harvard Medical School

Massachusetts General Hospital

Isaac Brownell

National Institutes of Health

Donald P. Lawrence

Massachusetts General Hospital

Harvard Medical School

Published

February 4, 2023

Featured Article

Overall survival with first-line atezolizumab in combination with vemurafenib and cobimetinib in BRAFV600 mutation- positive advanced melanoma (IMspire150): second interim analysis of a multicentre, randomised, phase 3 study. Ascierto et al. Lancet Oncology 2023 January; 24(1):33-44 8;387(23):2113-2125.

Introduction

On February 3^rd, 2023 the multi-institutional Community of Cutaneous Oncology (CCO) Journal Club reviewed the recently published Lancet Oncology article “Overall survival with first-line atezolizumab in combination with vemurafenib and cobimetinib in BRAFV600 mutation- positive advanced melanoma (IMspire150): second interim analysis of a multicentre, randomised, phase 3 study”(Ascierto et al. 2023). Participants included clinicians and investigators from Massachusetts General Hospital, Mass Eye and Ear, Brigham and Women’s Hospital, the National Institutes of Health, George Washington Medical Center, and Pennsylvania Hospital. Importantly, the comments in this article represent the views of the authors of this Perspectives on the Science piece after the Journal Club. It does not represent views of any other members of the CCO or the affiliated institutions. In this article we provide a summary of the discussion regarding this important contribution to the literature.

Background for the Study

The treatment landscape for advanced melanoma has changed rapidly over the last ten years (Figure 1)(D. M. Miller et al. 2022). Options for patients with advanced disease include immune-directed therapies, such as anti-PD-1(L1), anti-CTLA-4 and anti-LAG-3 monoclonal antibodies, as well as oncogene-pathway targeted therapies (TT) for patients with actionable mutations, including kinase inhibitors directed at BRAF and MEK (D. Miller, Flaherty, and Tsao 2014). Although dual BRAF/MEK inhibition (BRAFi/MEKi) is generally associated with higher response rates (Figure 2), immune checkpoint inhibitors (ICI) have become a preferred first-line strategy for most patients with advanced disease due to the potential for durable responses (Figures 2, 3 and 4).

Figure 1. Evolving treatment landscape in advanced melanoma.

Figure 1 Legend: Depicted are the therapies for advanced melanoma with FDA approval. Therapies approved for use in the post-resection, adjuvant setting were omitted.

Figure 2. Objective response rates of therapies for advanced melanoma

Figure 2 Legend: Depicted are the best overall response rates (BORR) of various therapeutics used to treat advanced melanoma. The study from which the data is derived is noted parenthetically. The graph is color-coded by the mechanism of action: “Immunotherapy” inculdes anti-PD-1, anti-CTLA4 mAbs, “Targeted Therapy” includes BRAF and MEK inhibitors and “Targeted Therapy + Immunotherapy” includes BRAF/MEK/PD-L1 directed agents. NIVO1/IPI3 represents a dosing regiment of nivolumab 1 mg/kg and ipilimumab 3 mg/kg every three weeks. NIVO3/IPI1 represents a dosing regiment of nivolumab 3 mg/kg and ipilimumab 1 mg/kg every three weeks. Of note, cross-trial comparisons should be made with caution.

Figure 3. BORR vs. PFS of therapies for advanced melanoma

Figure 3 Legend: Depicted are the best overall response rates (BORR) versus median Progression-Free Survival (PFS) of various therapeutics used to treat advanced melanoma. The graph is color-coded by the mechanism of action: “Immunotherapy” inculdes anti-PD-1, anti-CTLA4 mAbs, “Targeted Therapy” includes BRAF and MEK inhibitors and “Targeted Therapy + Immunotherapy” includes BRAF/MEK/PD-L1 directed agents. NIVO1/IPI3 represents a dosing regiment of nivolumab 1 mg/kg and ipilimumab 3 mg/kg every three weeks. NIVO3/IPI1 represents a dosing regiment of nivolumab 3 mg/kg and ipilimumab 1 mg/kg every three weeks. Of note, cross-trial comparisons should be made with caution.

Figure 4. BORR vs. Overall Survival of therapies for advanced melanoma

Figure 4 Legend: Depicted are the best overall response rates (BORR) versus median Overall Survival (OS) of various therapeutics used to treat advanced melanoma. The graph is color-coded by the mechanism of action: “Immunotherapy” inculdes anti-PD-1, anti-CTLA4 mAbs, “Targeted Therapy” includes BRAF and MEK inhibitors and “Targeted Therapy + Immunotherapy” includes BRAF/MEK/PD-L1 directed agents. The size of the points is representative to the number of subjects in that group. NIVO1/IPI3 represents a dosing regiment of nivolumab 1 mg/kg and ipilimumab 3 mg/kg every three weeks. NIVO3/IPI1 represents a dosing regiment of nivolumab 3 mg/kg and ipilimumab 1 mg/kg every three weeks. Of note, cross-trial comparisons should be made with caution.

Unfortunately, therapeutic options in the second-line setting have yielded sub-optimal results (Kim et al. 2023), highlighting the need to optimize front-line therapy. Given the potential to improve the response rates associated with ICIs and the durability of oncogene-pathway directed therapy, efforts to combine immunotherapy with targeted therapy have been ongoing for over a decade. Mechanistic rationale for combining BRAFi/MEKi with immune checkpoint inhibitors includes priming of the tumor microenvironment for immunotherapy via upregrulation of programmed death 1 ligand (PD-L1), increasing lymphocyte traffic and reduction of anti-inflammatory cytokines(Frederick et al. 2013; Wilmott et al. 2012; Schilling and Paschen 2013; Long et al. 2013; Boni et al. 2010; Kono et al. 2006; Sapkota, Hill, and Pollack 2013; Vella et al. 2014; Cooper et al. 2013). Initial investigations combining ICI with TT, however, highlighted the potential risk of enhanced toxicity. One early study of combination ipilimumab and vemurafenib reported the development of hepatoxicity in a significant portion of patients(Ribas et al. 2013). Subsequent studies demonstrated that BRAFi/MEKi could be safely administered with anti-PD-1(L1) monoclonal antibodies (Sullivan et al. 2019; Ferrucci et al. 2020; Dummer et al. 2022). IMspire150, a double-blinded, randomized, placebo-controlled, demonstrated improved median progression-free survival (PFS) of combination vemurafenib/cobimetinib/atezolizumab (vem/cobi/atezo) compared with vemurafenib/cobimetinib (vem/cobi) alone (15.1 vs 10.6 months HR: 0.78 (95% CI 0.63 - 0.97))(Gutzmer et al. 2020). Triplet therapy (BRAFi/MEKi/αPD-L1) was associated with more grade 3 or greater treatment-related adverse events (TRAEs) (Figure 5). However, the risk-to-benefit trade off was deemed acceptable and these results led to the FDA approval of this triplet therapy on July 30, 2020.

Figure 5. Treatment Related AEs vs. Overall Survival of therapies for advanced melanoma

Figure 5 Legend: Depicted are the CTCAE Grade 3 or greater Treatment-Related Adverse Events (TRAE) versus Overall Survival (OS) of various therapeutics used to treat advanced melanoma. The graph is color-coded by the mechanism of action: “Immunotherapy” includes anti-PD-1, anti-CTLA4 mAbs, “Targeted Therapy” includes BRAF and MEK inhibitors and “Targeted Therapy + Immunotherapy” includes BRAF/MEK/PD-L1 directed agents. The size of the points is representative to the number of subjects in that group. NIVO1/IPI3 represents a dosing regiment of nivolumab 1 mg/kg and ipilimumab 3 mg/kg every three weeks. NIVO3/IPI1 represents a dosing regiment of nivolumab 3 mg/kg and ipilimumab 1 mg/kg every three weeks. Of note, cross-trial comparisons should be made with caution.

Additional investigations have evaluated the safety and efficacy of triplet BRAFi/MEKi/αPD-1(L1) therapy. KEYONTE-022, a phase 2 trial of dabrafenib/trametinib (dab/tram) plus pembrolizumab vs. dab/tram/placebo, demonstrated improved PFS, OS and duration of response (DOR) with triplet therapy (Ferrucci et al. 2020). Notably DOR was more than double with triplet therapy (25.1 vs. 12.1 months; HR = 0.32) compared with doublet TT. Similarly in COMBI-i, a phase III trial evaluating the anti-PD-1 mAb spartalizumab plus dab/tam, demonstrated improved PFS with triplet therapy compared to BRAFi/MEKi (16.2 vs. 12.0 months; HR=0.82 (95%CI 0.66 to 1.03)), although that endpoint was not statistically significant(Dummer et al. 2022). Taken collectively, triplet therapy with BRAFi/MEKi/αPD-1(L1) likely improves PFS compared to BRAFi/MEKi (Figure 6), but at the expense of enhanced toxicity (Figure 7). The effect on overall survival (0S) has less supporting data. The interim results of IMspire150 report on that important endpoint.

Figure 6. BORR vs. PFS of various approaches to advanced melanoma treatment

Figure 7. Treatment Related AEs vs. median PFS of various approaches to advanced melanoma treatment

Study Design

IMspire150 is a multi-center, phase III randomized study. 514 patients with advanced BRAF V600-mutant melanoma were randomized into treatment groups consisting of cobimetinib 60 mg once daily with vemurafenib 960 mg twice daily for 21 days followed by vemurafenib 720 mg twice daily(triplet therapy group) or 960 mg twice daily (doublet therapy group) for 7 days (Figure 8). The triplet therapy group then received atezolizumab from cycle 2 and beyond. The doublet therapy group instead received placebo from cycle 2 onwards. As previously published, the primary endpoint was investigator-assessed PFS, with OS as a prespecified interim analysis. OS is the focus of this most recent report. Hazard Ratios (HRs) for PFS and OS survival were estimated using a stratified Cox model.

Figure 8. IMspire150 Study Design

flowchart LR

classDef leaf1 fill:#E5BDE7

IMspire150{{IMspire150 <br> Advanced BRAF V600 Mutant Melanoma<br> n = 514}}

IMspire150--Treatment Group--> triplet(Vem/Cobi/Atezolizumab <br> n = 256)


IMspire150--Control Group--> doublet(Vem/Cobi/Placebo <br> n = 258)

primaryEndpoint[Primary Endpoint - Progression Free Survival <br> Prespecified Interim Analysis - Overall Survival]:::leaf1

Study Results

At the data cutoff of September 8th, 2021, 273 patients who entered the study ha died. 126 deaths occurred in the triplet therapy group compared with 147 in the control group. Median overall survival was 39.0 months in the treatment group compared with 22.8 months in the control group. The Cox model HR for OS was 0.84 (95% CI 0.66 - 1.06, p = 0.14). Median PFS was 15.1 vs. 10.6, in favor of vem/cobi/atezo group. The most common cause of death was disease progression. No new safety signals were reported.

Discussion

Due to the rapid evolution in treatment for melanoma, clinicians have a variety of front-line options for advanced disease. A survey of the multi-institutional and multi-disciplinary group of CCO members present at the February 3^rd Journal Club (Figures 9-11) underscores the diversity of current approaches used by melanoma oncologists.

Figure 9. Journal club attendees

Figure 10. Attendees melanoma patient care experience

Figure 11. Attendees advanced melanoma patient care experience

When presented with a case of oligometastatic BRAF V600E melanoma, dual immune checkpoint inhibition was the most commonly recommended approach, with a third of respondents stating they would choose an αCTLA4/αPD-1 regimen, and another third recommending an αLAG-3/αPD-1 regimen. Only one respondent favored single agent αPD-1(L1), with one other selecting a BRAFi/MEKi-based strategy (Figure 12).

Figure 12. Management approach to oligometastatic melanoma

Not surprisingly, the majority of melanoma clinicians (71%, 5/7) selected an αCTLA4/αPD-1 based strategy for a patient with more significant tumor burden, including intracranial disease (Figure 13). CCO members cited the results from CheckMate-204 as rationale for front-line Ipi/Nivo for patients with brain metastases (Hussein A. Tawbi et al. (2018)). None of the attendees would have selected a regimen including both BRAFi/MEKi and immunotherapy six months ago (i.e. before the results of this paper) for either clinical scenario. Indeed, the overall experience with triplet therapy was limited, with only one practioner having recommended BRAFi/MEKi/αPD-1 outside of a clinical trial previously (Figure 14).

Figure 13. Management approach to high tumor burden metastatic melanoma

Figure 14. Experience with triplet therapy for melanoma

For many years there was little high-quality data guiding clinician’s initial treatment strategy selection for patients with advanced BRAF V600 mutant disease. Due to the potential of durable responses with immunotherapy, ICI was often chosen as the initial approach despite not having randomized, controlled data to support this decision. However, data from the recently published Phase III DREAMseq trial has helped fill this important information gap. Two-year OS rates were superior for BRAF V600 mutant patients treated initially with αCTLA4/αPD-1 compared with front-line BRAFi/MEKi (71.8% vs 51.5%, p = 0.01) (Atkins et al. 2023). Median duration of response (mDOR) was also significantly greater with upfront ICI compared with initial TT (mDOR not reached for the initial Ipi/Nivo group vs. 12.7 months for the initial BRAFi/MEKi group, p <0.001). These data reinforce the importance of sequencing therapy appropriately in patients with advanced disease.

The totality of the evidence from IMspire150, Keynote-022 and COMBI-i suggests that the addition of αPD-1(L1) therapy to a BRAFi/MEKi backbone yields improvement in PFS (and possibly OS) at a cost of added toxicity. The major limitation of these studies is that in the current treatment environment - largely solidified by the DREAMseq trial - the control groups (BRAFi/MEKi) are no longer a preferred initial regimen for the majority of patients with advanced, untreated BRAF V600 melanoma. Thus, despite a signal in all three studies that adding αPD-1(L1) to BRAFi/MEKi improves patient outcomes, the role of triplet therapy in the first-line setting remains uncertain. A more relevant and clarifying comparator of front-line triplet therapy would be either monotherapy αPD-1(L1) or dual ICB, given that ICI is being used in the initial management plan for most patients. The operative question being whether adding targeted therapy to an immunotherapy-based regimen produces improved outcomes compared to a front-line immunotherapy-only strategy. As a consequence of this important caveat, the borderline insignificant interim results of IMspire150 had little effect on the medical decision making of the CCO JC attendees (Figure 15). Given that the study was not answering a question critically important to practioners in 2023, the impact of the paper would have likely been the same had the hazard ratio for OS excluded the null hypothesis. To further support the lack of clarity on the role of triplet therapy after these interim results, respondents replied with similar treatment approaches to patients with oligo- (Figure 16) and more widespread (Figure 17) disease in the current day, as compared with six months ago (Figures 12-13). Again, none of the practioners selected triplet therapy for these clinical scenarios after discussing the recent update of IMspire150.

Figure 15. Practice changing nature of the study

Figure 16. The case of oligometastatic melanoma revisited

Figure 17. The case of high-tumor burden melanoma revisited

Although the clinical vignette of high-tumor burden disease did not elicit a selection of triplet therapy by any of the melanoma clinicians, the question of whether triplet therapy or even quadruple therapy (i.e. BRAFi/MEKi/αPD-1/αCTLA4) would be used in the case of impending visceral crisis was raised. Indeed, the one clinician with previous real-world experience with triplet therapy utilized concomitant BRAFi/MEKi/αPD-1 therapy in a patient with fulminant disease including widespread liver metastases and diffuse melanosis cutis. Fortunately that patient went on to have a complete response and is alive today. Patients that present with symptomatic brain metastases represent another cohort that may benefit from combination TT/ICI. While combination CTLA4/αPD-1 has shown impressive activity in patients with asymptomatic intracranial metastases, the efficacy of ipi/nivo is significantly attenuated in patients receiving corticosteroids for symptomatic disease(Hussein A. Tawbi et al. 2021). Therefore, there is rationale to treat with a lead-in of targeted therapy to decrease intracranial disease burden in order to expedite steroid tapering prior to the administration of immunotherapy. Thus, the discussion reinforced the importance of having options in the treatment armamentarium which can be applied on a case-by-case basis.

Materials and Methods

This Perspectives on the Science piece was published using Quarto^®. The survey was conducted using REDCap^® (Harris et al. 2009). The figures depicting the survey data were created using R (version 4.0.0) and the tidyverse suite of packages (Wickham et al. 2019), including ggplot2 (Wickham 2016). The figure depicting FDA approved therapies in melanoma was created using the skincancerRx package (D. Miller and Shalhout 2022).

Bibliography

References

Ascierto, Paolo A, Daniil Stroyakovskiy, Helen Gogas, Caroline Robert, Karl Lewis, Svetlana Protsenko, Rodrigo P Pereira, et al. 2023. “Overall Survival with First-Line Atezolizumab in Combination with Vemurafenib and Cobimetinib in BRAFV600 Mutation-Positive Advanced Melanoma (IMspire150): Second Interim Analysis of a Multicentre, Randomised, Phase 3 Study.” The Lancet Oncology 24 (1): 33–44. https://doi.org/10.1016/s1470-2045(22)00687-8.

Atkins, Michael B., Sandra J. Lee, Bartosz Chmielowski, Ahmad A. Tarhini, Gary I. Cohen, Thach-Giao Truong, Helen H. Moon, et al. 2023. “Combination Dabrafenib and Trametinib Versus Combination Nivolumab and Ipilimumab for Patients With Advanced BRAF-Mutant Melanoma: The DREAMseq TrialECOG-ACRIN EA6134.” Journal of Clinical Oncology 41 (2): 186–97. https://doi.org/10.1200/jco.22.01763.

Boni, Andrea, Alexandria P. Cogdill, Ping Dang, Durga Udayakumar, Ching-Ni Jenny Njauw, Callum M. Sloss, Cristina R. Ferrone, et al. 2010. “Selective BRAFV600E Inhibition Enhances T-Cell Recognition of Melanoma Without Affecting Lymphocyte Function.” Cancer Research 70 (13): 5213–19. https://doi.org/10.1158/0008-5472.can-10-0118.

Cooper, Zachary A, Dennie T Frederick, Vikram R Juneja, Ryan J Sullivan, Donald P Lawrence, Adriano Piris, Arlene H Sharpe, David E Fisher, Keith T Flaherty, and Jennifer A Wargo. 2013. “BRAF Inhibition Is Associated with Increased Clonality in Tumor-Infiltrating Lymphocytes.” OncoImmunology 2 (10): e26615. https://doi.org/10.4161/onci.26615.

Dummer, Reinhard, Georgina V. Long, Caroline Robert, Hussein A. Tawbi, Keith T. Flaherty, Paolo A. Ascierto, Paul D. Nathan, et al. 2022. “Randomized Phase III Trial Evaluating Spartalizumab Plus Dabrafenib and Trametinib forBRAFV600Mutant Unresectable or Metastatic Melanoma.” Journal of Clinical Oncology 40 (13): 1428–38. https://doi.org/10.1200/jco.21.01601.

Ferrucci, Pier Francesco, Anna Maria Di Giacomo, Michele Del Vecchio, Victoria Atkinson, Henrik Schmidt, Jacob Schachter, Paola Queirolo, et al. 2020. “KEYNOTE-022 Part 3: A Randomized, Double-Blind, Phase 2 Study of Pembrolizumab, Dabrafenib, and Trametinib in BRAF-Mutant Melanoma.” Journal for ImmunoTherapy of Cancer 8 (2): e001806. https://doi.org/10.1136/jitc-2020-001806.

Frederick, Dennie T., Adriano Piris, Alexandria P. Cogdill, Zachary A. Cooper, Cecilia Lezcano, Cristina R. Ferrone, Devarati Mitra, et al. 2013. “BRAF Inhibition Is Associated with Enhanced Melanoma Antigen Expression and a More Favorable Tumor Microenvironment in Patients with Metastatic Melanoma.” Clinical Cancer Research 19 (5): 1225–31. https://doi.org/10.1158/1078-0432.ccr-12-1630.

Gutzmer, Ralf, Daniil Stroyakovskiy, Helen Gogas, Caroline Robert, Karl Lewis, Svetlana Protsenko, Rodrigo P Pereira, et al. 2020. “Atezolizumab, Vemurafenib, and Cobimetinib as First-Line Treatment for Unresectable Advanced BRAFV600 Mutation-Positive Melanoma (IMspire150): Primary Analysis of the Randomised, Double-Blind, Placebo-Controlled, Phase 3 Trial.” The Lancet 395 (10240): 1835–44. https://doi.org/10.1016/s0140-6736(20)30934-x.

Harris, Paul A., Robert Taylor, Robert Thielke, Jonathon Payne, Nathaniel Gonzalez, and Jose G. Conde. 2009. “Research Electronic Data Capture (REDCap)A Metadata-Driven Methodology and Workflow Process for Providing Translational Research Informatics Support.” Journal of Biomedical Informatics 42 (2): 377–81. https://doi.org/10.1016/j.jbi.2008.08.010.

Kim, Emily Y, Sophia Z. Shalhout, Howard L. Kaufman, Kevin S. Emerick, Vishal A. Patel, Khalid Garmen, Isaac Brownell, and David M. Miller. 2023. “Tumor-Infiltrating Lymphocyte Therapy for Advanced Melanoma: Ready for Prime Time?” Journal of Cutaneous Oncology 1 (1). https://journalofcutaneousoncology.io/perspectives/til_therapy_for_advanced_melanoma.

Kono, Michihiro, Ian S. Dunn, Paul J. Durda, David Butera, Lenora B. Rose, Timothy J. Haggerty, Elizabeth M. Benson, and James T. Kurnick. 2006. “Role of the Mitogen-Activated Protein Kinase Signaling Pathway in the Regulation of Human Melanocytic Antigen Expression.” Molecular Cancer Research 4 (10): 779–92. https://doi.org/10.1158/1541-7786.mcr-06-0077.

Long, Georgina V., James S. Wilmott, Lauren E. Haydu, Varsha Tembe, Raghwa Sharma, Helen Rizos, John F. Thompson, Julie Howle, Richard A. Scolyer, and Richard F. Kefford. 2013. “Effects of BRAF Inhibitors on Human Melanoma Tissue Before Treatment, Early During Treatment, and on Progression.” Pigment Cell & Melanoma Research 26 (4): 499–508. https://doi.org/10.1111/pcmr.12098.

Miller, David M, Sophia Z Shalhout, Denise Casey, Lola Fashoyin-Aje, Steven Lemery, Marc R Theoret, and Richard Pazdur. 2022. “Impact of an Evolving Regulatory Landscape on Skin Cancer Drug Development in the u.s.” Dermatology Online Journal 28 (2). https://doi.org/10.5070/d328257391.

Miller, David, Keith Flaherty, and Hensin Tsao. 2014. “Current Status and Future Directions of Molecularly Targeted Therapies and Immunotherapies for Melanoma.” Seminars in Cutaneous Medicine and Surgery 33 (2): 60–67. https://doi.org/10.12788/j.sder.0081.

Miller, David, and Sophia Shalhout. 2022. skincancerRx: Generates Visualizations for Data Related to FDA Approvals in Skin Cancer.

Ribas, Antoni, F. Stephen Hodi, Margaret Callahan, Cyril Konto, and Jedd Wolchok. 2013. “Hepatotoxicity with Combination of Vemurafenib and Ipilimumab.” New England Journal of Medicine 368 (14): 1365–66. https://doi.org/10.1056/nejmc1302338.

Sapkota, Bishu, Charles E. Hill, and Brian P. Pollack. 2013. “Vemurafenib Enhances MHC Induction inBRAF^V600Ehomozygous Melanoma Cells.” OncoImmunology 2 (1): e22890. https://doi.org/10.4161/onci.22890.

Schilling, Bastian, and Annette Paschen. 2013. “Immunological Consequences of Selective BRAF Inhibitors in Malignant Melanoma.” OncoImmunology 2 (8): e25218. https://doi.org/10.4161/onci.25218.

Sullivan, Ryan J., Omid Hamid, Rene Gonzalez, Jeffrey R. Infante, Manish R. Patel, F. Stephen Hodi, Karl D. Lewis, et al. 2019. “Atezolizumab Plus Cobimetinib and Vemurafenib in BRAF-Mutated Melanoma Patients.” Nature Medicine 25 (6): 929–35. https://doi.org/10.1038/s41591-019-0474-7.

Tawbi, Hussein A., Peter A. Forsyth, Alain Algazi, Omid Hamid, F. Stephen Hodi, Stergios J. Moschos, Nikhil I. Khushalani, et al. 2018. “Combined Nivolumab and Ipilimumab in Melanoma Metastatic to the Brain.” New England Journal of Medicine 379 (8): 722–30. https://doi.org/10.1056/nejmoa1805453.

Tawbi, Hussein A, Peter A Forsyth, F Stephen Hodi, Christopher D Lao, Stergios J Moschos, Omid Hamid, Michael B Atkins, et al. 2021. “Safety and Efficacy of the Combination of Nivolumab Plus Ipilimumab in Patients with Melanoma and Asymptomatic or Symptomatic Brain Metastases (CheckMate 204).” Neuro-Oncology 23 (11): 1961–73. https://doi.org/10.1093/neuonc/noab094.

Vella, Laura J., Anupama Pasam, Nektaria Dimopoulos, Miles Andrews, Ashley Knights, Anne-Laure Puaux, Jamila Louahed, Weisan Chen, Katherine Woods, and Jonathan S. Cebon. 2014. “MEK Inhibition, Alone or in Combination with BRAF Inhibition, Affects Multiple Functions of Isolated Normal Human Lymphocytes and Dendritic Cells.” Cancer Immunology Research 2 (4): 351–60. https://doi.org/10.1158/2326-6066.cir-13-0181.

Wickham, Hadley. 2016. Ggplot2: Elegant Graphics for Data Analysis. Springer-Verlag New York. https://ggplot2.tidyverse.org.

Wickham, Hadley, Mara Averick, Jennifer Bryan, Winston Chang, Lucy D’Agostino McGowan, Romain François, Garrett Grolemund, et al. 2019. “Welcome to the Tidyverse” 4: 1686. https://doi.org/10.21105/joss.01686.

Wilmott, James S., Georgina V. Long, Julie R. Howle, Lauren E. Haydu, Raghwa N. Sharma, John F. Thompson, Richard F. Kefford, Peter Hersey, and Richard A. Scolyer. 2012. “Selective BRAF Inhibitors Induce Marked T-Cell Infiltration into Human Metastatic Melanoma.” Clinical Cancer Research 18 (5): 1386–94. https://doi.org/10.1158/1078-0432.ccr-11-2479.

Appendix

Disclosures, Disclaimer, License

Disclosures

DMM reports grants and personal fees from Regeneron, grants from Kartos Therapeutics, grants from NeoImmuneTech, personal fees from Checkpoint Therapeutics, personal fees from Pfizer, personal fees from Merck Sharpe & Dome, personal fees from EMD Serono, grants from Project DataSphere, personal fees from Sanofi Genzyme, personal fees from Castle Biosciences, personal fees from Avstera, outside the submitted work. EYK and SZS report no competing interests. HLK is an employee of Ankyra Therapeutics and serves on advisory boards for Marengo Therapeutics, Castle Bioscience, Virogin and MidaTech Pharma. VAP reports consulting honorarium from Regeneron, PhD Biosciences, Jounce Therapeutics, Almirall, and Castle Biosciences, and stock options from Avstera and Lazarus AI.

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BibTeX citation:

@article{m.miller2023,
  author = {David M. Miller and Kevin S. Emerick and Vishal A. Patel and
    Sonia Cohen and Isaac Brownell and Donald P. Lawrence},
  publisher = {Community of Cutaneous Oncology},
  title = {Lacking {Overall} {IMspiration} for {Triplet} {Therapy} in
    {Melanoma?} {A} {Review} of the {Interim} {Analysis} of
    {IMspire150.}},
  journal = {Journal of Cutaneous Oncology},
  volume = {1},
  number = {1},
  date = {2023-02-04},
  url = {https://journalofcutaneousoncology.io/perspectives/triplet_therapy_for_advanced_melanoma/},
  issn = {pending},
  langid = {en}
}

For attribution, please cite this work as:

David M. Miller, Kevin S. Emerick, Vishal A. Patel, Sonia Cohen, Isaac Brownell, and Donald P. Lawrence. 2023. “Lacking Overall IMspiration for Triplet Therapy in Melanoma? A Review of the Interim Analysis of IMspire150.” Journal of Cutaneous Oncology 1 (1). https://journalofcutaneousoncology.io/perspectives/triplet_therapy_for_advanced_melanoma/.